19-13135228-G-C

Variant names:

• chr19-13135228-G-C
• NM_052876.4:c.21G>C
• NACC1 p.Met7Ile

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_052876.4(NACC1):​c.21G>C​(p.Met7Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NACC1 NM_052876.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.17
• Publications: 0 publications found

Genes affected

NACC1 (HGNC:20967): (nucleus accumbens associated 1) This gene encodes a member of the BTB/POZ protein family. BTB/POZ proteins are involved in several cellular processes including proliferation, apoptosis and transcription regulation. The encoded protein is a transcriptional repressor that plays a role in stem cell self-renewal and pluripotency maintenance. The encoded protein also suppresses transcription of the candidate tumor suppressor Gadd45GIP1, and expression of this gene may play a role in the progression of multiple types of cancer. A pseudogene of this gene is located on the short arm of chromosome 9. [provided by RefSeq, Feb 2012]

NACC1 Gene-Disease associations (from GenCC):

• NACC1-related neurodevelopmental disorder with epilepsy, cataracts and episodic irritability

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1641455).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_052876.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NACC1	NM_052876.4	MANE Select	c.21G>C	p.Met7Ile	missense	Exon 2 of 6	NP_443108.1	Q96RE7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NACC1	ENST00000292431.5	TSL:1 MANE Select	c.21G>C	p.Met7Ile	missense	Exon 2 of 6	ENSP00000292431.3	Q96RE7
	NACC1	ENST00000586171.3	TSL:5	c.21G>C	p.Met7Ile	missense	Exon 3 of 7	ENSP00000467120.2	Q96RE7
	NACC1	ENST00000700232.1		c.21G>C	p.Met7Ile	missense	Exon 2 of 6	ENSP00000514870.1	Q96RE7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0051	T
Eigen	Benign	-0.23
Eigen_PC	Benign	0.00052
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.20	N
PhyloP100		4.2
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.53	N
REVEL	Benign	0.11
Sift	Benign	0.60	T
Sift4G	Benign	0.46	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.50
gMVP		0.79
Mutation Taster		=15/85	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr19-13246042;